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Relative DOPA Deficiency in Lightly Pigmented Skin Contributes to UV-Independent Melanoma Susceptibility

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Relative DOPA Deficiency in Lightly Pigmented Skin Contributes to UV-Independent Melanoma Susceptibility bioRxiv preprint doi: https://doi.org/10.1101/2021.03.03.433757; this version posted March 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Relative DOPA Deficiency in Lightly Pigmented Skin Contributes to UV-Independent Melanoma Susceptibility Miriam Doepner1, Christopher A. Natale1, Todd W. Ridky1* 1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. USA *Correspondence to: [email protected] Abstract Melanoma risk is higher for people with lightly pigmented skin (1:38) compared to those with darkly pigmented skin (1:1000). While this difference is typically attributed to the ultraviolet radiation (UVR) shielding effect of melanin pigment, here we show that other cell-intrinsic differences between dark and light MCs, independent of melanin and UV, regulate MC proliferative capacity, cellular differentiation state, and susceptibility to malignant transformation. These differences are driven by dihydroxyphenylalanine (DOPA), a melanin synthesis intermediate, and result from DOPA antagonism of the muscarinic acetylcholine receptor M1 (CHRM1), a G Protein-Coupled Receptor (GPCR) expressed in MCs, but not previously known to bind DOPA, nor to affect melanoma pathobiology. Pharmacologic CHRM1 antagonism in melanoma leads to downregulation of c-Myc and FOXM1, both of which are proliferation drivers associated with aggressive melanoma. In preclinical melanoma models, pharmacologic CHRM1 inhibition in vivo inhibited melanoma growth. CHRM1 may be a new therapeutic target for melanoma. Statement of Significance A previously unrecognized ability of dihydroxyphenylalanine (DOPA) to inhibit the muscarinic acetylcholine receptor M1 (CHRM1) in melanocytes contributes to decreased melanoma susceptibility in darkly pigmented skin, independent of ultraviolet exposure. Pharmacologic CHRM1 inhibition inhibits melanoma in preclinical melanoma models, indicating that CHRM1 may be a new therapeutic target for melanoma. Introduction Melanoma is the most lethal form of skin cancer and worldwide incidence is increasing. Despite advances in modern immune and targeted therapies, most patients with metastatic melanoma still die from their disease and new treatment approaches are needed.1,2 Clues to new therapeutic approaches may lie in understanding the mechanisms by which melanoma differentially affects different populations of people. Here we consider why the lifetime risk for cutaneous melanoma is substantially higher for people with lightly pigmented skin compared to those with darkly pigmented skin, even when they live in the same geographic region and are thereby exposed to similar amounts of UVR.3 Melanoma develops from melanocytes (MCs), which normally reside in the basal layer of skin and hair follicles where they produce melanin pigment, the primary determinant of skin and hair color. Melanogenesis is a complex, multi-step process that begins with the non-essential amino acid L-tyrosine and results in the 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.03.433757; this version posted March 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. production of mostly insoluble eumelanin (brown-black) or pheomelanin (red-yellow) polymers.4–6 Variation in the eumelanin to pheomelanin ratio creates the natural diversity in human skin pigmentation. These baseline pigmentary differences result from numerous single nucleotide polymorphisms (SNPs) in at least 200 genes involved in melanin synthesis.7 Eumelanin acts as a physical photoprotective filter against DNA damaging solar ultraviolet radiation (UVR) and thereby protects skin cells from deleterious mutations that may lead to malignant transformation.8 While melanin’s UVR shielding effect undoubtedly accounts for some of the difference of the lifetime melanoma risk, highly pigmented skin provides a sun protective factor (SPF) of only 2- 3 versus lightly pigmented skin, which seems insufficient to completely explain the large difference in skin cancer incidence between people with lightly pigmented vs darkly pigmented skin.9,10 Furthermore, a UVR shielding effect does not fully explain decades of epidemiologic data suggesting that there are UV-independent determinants of melanoma risk that also correlate with skin pigment type. Melanomas arising in completely sun-protected areas, such as anorectal melanoma, are 13-fold higher in people with lightly pigmented skin than those with darkly pigmented skin.11,12 There is also an intriguing observation involving skin cancer in people from Africa with albinism. While affected individuals have epidermal MCs, they do not make melanin, and therefore have white or extremely lightly pigmented skin and hair. They exhibit photosensitivity and an expected elevated incidence of keratinocyte-derived cancers, including basal cell and squamous cell carcinomas. However, they appear highly resistant to melanoma suggesting that while their MCs are visibly light, they may be functionally “dark” with regard to melanoma, and thereby similar to those with darkly pigmented skin in their population group with shared African ancestry.13,14 The mechanism(s) underlying these apparent UV-independent determinants of melanoma susceptibility are unknown. Here, we show that dihydroxyphenylalanine (DOPA), a melanin synthesis intermediate, drives differentiation in primary human MCs, that is associated slower proliferation and resistance to the oncogenic effects of the major human melanoma oncoprotein BRAF(V600E). We show that DOPA functions to antagonize the muscarinic acetylcholine receptor M1 (CHRM1), a G Protein-Coupled Receptor (GPCR), that is necessary and sufficient for DOPA’s anti-proliferative effect. In preclinical melanoma models, pharmacologic CHRM1 inhibition in vivo inhibited melanoma growth, suggesting that CHRM1 antagonists may represent a previously unrecognized class of melanoma therapeutics. Results Darkly pigmented MCs are less tumorigenic than light pigmented MCs Under standard cell culture conditions without UVR, lightly pigmented early passage primary human MCs (LMC) proliferated 2-3 times faster than darkly pigmented MCs (DMC) (Figure 1A). Melanocyte proliferative capacity is classically inversely correlated with MC cellular differentiation state15–19, which is primarily regulated 20–23 by the activation of Gs-coupled G protein-coupled receptors (GPCRs). Gs signaling stimulates production of cyclic adenosine monophosphate (cAMP) via adenylate cyclase. In MCs, cAMP activates protein kinase A (PKA), which phosphorylates and activates the cAMP response element-binding protein (CREB), which ultimately promotes downstream synthesis of proteins involved in melanin production, such as tyrosinase 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.03.433757; this version posted March 4, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. (Tyr).24,25 We examined whether the expression of proteins within this classic GPCR pathway differed between LMCs and DMCs. DMCs expressed lower levels of phosphorylated CREB (pCREB) and tyrosinase, as compared to light MCs (Supplemental Figure 1A), suggesting that DMCs are more fully advanced along a cellular differentiation continuum that parallels the natural range of human skin pigment diversity. Consistent with this idea, DMCs expressed less of the stem cell marker and oncoprotein c-Myc (Figure 1B, Supplemental Figure 1A). We hypothesized that these baseline differences in relative cellular differentiation state and proliferative capacity between DMCs and LMCs contribute to overall differential melanoma susceptibility. To test this in vivo, we used a genetically defined orthotopic human melanoma (heMel) model.26,27 Primary LMC and DMCs were engineered via lentivirus to express mutant oncoproteins associated with spontaneous human melanoma including BRAFV600E, dominant-negative p53R248W, active CDK4R24C, and hTERT26. Equal expression of all oncoproteins was confirmed in darkly pigmented and lightly pigmented heMel cells (Supplemental Figure 1C). The proliferation and differentiation differences between DMCs and LMCs observed in the untransduced parental cells remained after transduction of the oncoproteins. Darkly pigmented heMel cells proliferated over two times slower than lightly pigmented heMel cells and maintained their more differentiated phenotype (Figure 1C, Supplemental Figure 1B), suggesting that cell intrinsic factors in DMCs may protect them from the oncogenic effects of common melanoma drivers. To test whether these in vitro differences translated to different melanoma phenotypes in vivo, lightly and darkly pigmented heMel cells were combined with primary human keratinocytes and incorporated into devitalized human dermis to establish 3-dimensional skin tissues in organotypic culture.28 We then grafted the engineered skin onto the orthotopic location on the backs of female severe combined immunodeficient (SCID) mice. After 100 days, the grafts were harvested and analyzed histologically. Tissues with lightly pigmented heMel cells formed early melanomas, with large proliferative melanocytic nests with hallmark melanoma features, including early dermal invasion and upward Pagetoid scatter (Figure 1D, E). In
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